title: Alterations of brain and cerebellar proteomes linked to Aβ and tau pathology in a female triple-transgenic murine model of Alzheimer's disease.
abstract: The triple-transgenic Alzheimer (3 × Tg-AD) mouse expresses mutant PS1(M146V), APP(swe), and tau(P301L) transgenes and progressively develops plaques and neurofibrillary tangles with a temporal- and region-specific profile that resembles the neuropathological progression of Alzheimer's disease (AD). In this study, we used proteomic approaches such as two-dimensional gel electrophoresis and mass spectrometry to investigate the alterations in protein expression occurring in the brain and cerebellum of 3 × Tg-AD and presenilin-1 (PS1) knock-in mice (animals that do not develop Aβ- or tau-dependent pathology nor cognitive decline and were used as control). Finally, using the Ingenuity Pathway Analysis we evaluated novel networks and molecular pathways involved in this AD model. We identified several differentially expressed spots and analysis of 3 × Tg-AD brains showed a significant downregulation of synaptic proteins that are involved in neurotransmitter synthesis, storage and release, as well as a set of proteins that are associated with cytoskeleton assembly and energy metabolism. Interestingly, in the cerebellum, a structure not affected by AD, we found an upregulation of proteins involved in carbohydrate metabolism and protein catabolism. Our findings help to unravel the pathogenic brain mechanisms set in motion by mutant amyloid precursor protein (APP) and hyperphosphorylated tau. These data also reveal cerebellar pathways that may be important to counteract the pathogenic actions of Aβ and tau, and ultimately offer novel targets for therapeutic intervention.
authors.affiliation: Molecular Neurology Unit, Center of Excellence on Aging, University G. d'Annunzio, Chieti, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Ciavardelli
authors.forename: E
authors.initials: E
authors.lastname: Silvestri
authors.forename: A
authors.initials: A
authors.lastname: Del Viscovo
authors.forename: M
authors.initials: M
authors.lastname: Bomba
authors.forename: D
authors.initials: D
authors.lastname: De Gregorio
authors.forename: M
authors.initials: M
authors.lastname: Moreno
authors.forename: C
authors.initials: C
authors.lastname: Di Ilio
authors.forename: F
authors.initials: F
authors.lastname: Goglia
authors.forename: L M T
authors.initials: LM
authors.lastname: Canzoniero
authors.forename: S L
authors.initials: SL
authors.lastname: Sensi
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism*; D004195:Disease Models, Animal; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D055879:Gene Knock-In Techniques; D051379:Mice; D008822:Mice, Transgenic; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D020543:Proteome / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D020543:Proteome; D016875:tau Proteins